Pre-plaque conformational changes in Alzheimer's disease-linked Aß and APP.

Reducing levels of the aggregation-prone Aß peptide that accumulates in the brain with Alzheimer's disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of Aß. To date, the physiological state of Aß in brain remains unclear, since the available methods used to process brain tissue for determination of Aß aggregate conformation can in themselves alter the structure and/or composition of the aggregates. Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Aß and amyloid precursor protein (APP) in brain of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal Aß aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of Aß and APP that occur prior to plaque formation may provide novel targets for AD therapy.

Role of alcohol, glucose intolerance and obesity in hypertriglyceridemia.

From a primary health screening 631 subjects with serum triglycerides greater than or equal to 4.0 mmol/l were investigated for underlying factors for hypertriglyceridemia. Obesity, glucose intolerance, or suspected high alcohol consumption were associated in 84.5% if the definitions were: Actual/ideal weight (A/I) greater than or equal to 1.2 (obesity), blood glucose in the fasting state or after 120 min of an oral glucose tolerance test (OGTT) greater than or equal to 7.0 mmol/l (glucose intolerance), and gammaglutamyltransferase (GGT) greater than or equal to 1.0 mu kat/l (suspected high alcohol consumption). Ninety-seven percent were associated if also those with positive alcohol anamnesis or with A/I 1.06-1.19, blood glucose after 120 min of an OGTT 6.5-6.99, or GGT 0.8-0.99 were included.

Homocysteine and myocardial infarction.

Five (24%) subjects out of a group of 21 men, 48-58 years old (mean 54), who had suffered their first myocardial infarction (MI) before the age of 55 and with a low risk profile vis-à-vis conventional risk factors in a health screening preceding the MI, had abnormally high total plasma homocysteine values in the fasting state when investigated within 1-7 years (mean 3) after their MI. The patient group was exactly matched with 36 control subjects for sex, age, diastolic blood pressure, smoking, and serum concentrations of cholesterol and triglycerides. Total plasma homocysteine was negatively correlated to both erythrocyte folate and serum vitamin B12, and vitamin concentrations below the median of the normal distribution were found in the five with high plasma homocysteine content, indicating a possible involvement of reduced remethylation of plasma homocysteine to methionine. After methionine loading, in 3 of the patient group (14%) homocysteine levels exceeded mean +2 SD for controls, which may indicate heterozygosity for homocystinuria. Results are consistent with the hypothesis that a high plasma homocysteine content may be a risk factor for MI.

Influence of hydrolysis on plasma homocysteine determination in healthy subjects and patients with myocardial infarction.

After acid hydrolysis, mean plasma homocysteine concentrations, measured as homocysteine disulphides, of about 1000 and 40 mumol/l have recently been reported in 26 survivors of myocardial infarction and 26 matched control subjects, respectively. This finding contrasts sharply with those more than 50 times lower total homocysteine concentrations found by other research groups in non-hydrolysed plasma from survivors of myocardial infarction. Using the same hydrolysis conditions, we could not detect any homocysteine disulphides in plasma hydrolysates from 9 survivors of myocardial infarction and 10 healthy subjects, who had mean total homocysteine concentrations in non-hydrolysed plasma of 16.9 +/- 6.5 and 15.8 +/- 10.3 mumol/l, respectively. The chromatograms contained several peaks, probably representing peptides, which disappeared with more complete hydrolysis and which might have been misinterpreted as homocysteine disulphides in the reported study. Only after reduction of disulphides and by using a sulphydryl-selective extraction procedure were we able to determine mean homocysteine concentrations in hydrolysed plasma to be 26.2 +/- 7.9 mumol/l in the survivors of myocardial infarction and 24.5 +/- 12.2 mumol/l in the healthy reference subjects. Thus, we could not confirm that survivors of myocardial infarction have homocysteine concentrations that are many times higher than found in healthy subjects.

Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment.

Severe homocysteinemia due to genetic defects either of pyridoxal 5-phosphate (PLP)-dependent cystathionine beta-synthase (CBS) or of enzymes in vitamin B12 and folate metabolism is associated with very early-onset vascular disease. Therefore, we studied homocysteine metabolism in 72 patients presenting before the age of 55 years with occlusive arterial disease of cerebral, carotid, or aorto-iliac vessels. Twenty patients (28%) had basal homocysteinemia; and 26 patients (36%) had abnormal increases of plasma homocysteine after peroral methionine loading, which exceeded the highest value for 46 comparable controls and was within the range for 20 obligate heterozygotes for homocystinuria due to CBS deficiency. Basal plasma homocysteine content was strongly and negatively correlated to vitamin B12 and folate concentrations. Plasma PLP was depressed in most patients but there was no correlation between PLP and homocysteine values. In 20 patients, treatment with pyridoxine hydrochloride (240 mg/day) and folic acid (10 mg/day) reduced fasting homocysteine after 4 weeks by a mean of 53%, and methionine response by a mean of 39%. These data show that a substantial proportion of patients with early-onset vascular disease have impaired homocysteine metabolism, which may contribute to vascular disease, and that the impaired metabolism can be improved easily and without side effects.

Alcohol consumption and disability pension among middle-aged men.

PURPOSE: To analyze the relation between alcohol consumption and the risk of disability pension among middle-aged men. METHODS: In the mid-seventies, complete birth-year cohorts of middle-aged male residents in Malmö, Sweden, were invited to participate in a general health survey. The 3751 men with complete data who constituted the cohort in this study were followed for 11 years. Alcohol consumption was estimated from the scores obtained from a test designed to identify subjects with alcohol related problems. RESULTS: Of the 498 men granted disability pension during follow-up, 48 stated to be teetotalers. The cumulative incidence of disability pension among teetotalers was 19%, whereas, it was 12% and 16%, respectively, among men with low and high alcohol consumption. The adjusted relative risk (RR) for acquiring a disability pension (using the group with low alcohol consumption as reference) was 1.8 among abstainers and 1.3 among men with high alcohol consumption. CONCLUSIONS: Alcohol overconsumption, as well as teetotalism, showed a positive relation to disability pension, and a moderate alcohol intake was found to be beneficial with respect to the risk of future disability pension.

Socioeconomic inequalities and disability pension in middle-aged men.

BACKGROUND: The issue of inequalities in health has generated much discussion and socioeconomic status is considered an important variable in studies of health. It is frequently used in epidemiological studies, either as a possible risk factor or a confounder and the aim of this study was to analyse the relation between socioeconomic status and risk of disability pension. METHODS: Five complete birth year cohorts of middle-aged male residents in Malmo were invited to a health survey and 5782 with complete data constituted the cohort in this prospective study. Each subject was followed for approximately 11 years and nationwide Swedish data registers were used for surveillance. RESULTS: Among the 715 men (12%), granted disability pension during follow-up, three groups were distinguished. The cumulative incidence of disability pension among blue collar workers was 17% and among lower and higher level white collar workers, 11% and 6% respectively. With simultaneous adjustment for biological risk factors and job conditions, the relative risk for being granted a disability pension (using higher level white collar workers as reference) was 2.5 among blue collar workers and 1.6 among lower level white collar workers. CONCLUSIONS: Socioeconomic status, as defined by occupation, is a risk factor for being granted disability pension even after adjusting for work conditions and other risk factors for disease.

Body mass index and disability pension in middle-aged men--non-linear relations.

BACKGROUND: Obesity has, in a number of studies, been found to correlate to disability and mortality, primarily due to diseases of the circulatory and musculoskeletal systems. In addition, an excess mortality among underweight subjects has been observed in previous studies. METHODS: Five complete birth-year cohorts (1926-1930) of male residents in Malmö (n = 7697) were invited to the survey at the Department of Preventive Medicine, Malmö General Hospital, and 5926 (77%) attended with complete data. Each subject was followed from inclusion, defined by the date of examination, until the end of the calendar year when he turned 58, a total study period of approximately 11 years. Data on about 300 questionnaire items and laboratory tests were determined at the health survey visit. Nationwide Swedish data registers were used for surveillance. RESULTS: Of the participants, 4.7% were underweight, 37.7% overweight, 7.3% obese and 50.3% normal weight; 849 (14.3%) had been granted disability pension at the end of follow-up, 717 after screening. After adjustment for smoking there was a J-shaped relation between body mass index (BMI) and incidence of disability pension, the relative risk ( with the normal group as reference) among underweight men being 1.9. For the overweight subjects it was 1.3 and for the obese 2.8, all differences were significant. Disease of the musculoskeletal and circulatory systems and mental disorders accounted for 67.2% of all main diagnoses resulting in disability pensions during follow-up. A total of 377 (6.4%) men died during follow-up. Diseases of the circulatory system, neoplasms, injury/poisoning and diseases of the respiratory system accounted for 91.8% of the deaths. CONCLUSIONS: Both underweight, overweight and obesity were related to risk of disability pension, with a J-shaped risk relationship.

Effects of systematic education on heart failure patients' knowledge after 6 months. A randomised, controlled trial.

BACKGROUND: Many procedures for patient education are introduced in clinical practice without proper evaluation in randomised trials. AIMS: To compare systematic nurse and pharmacist led education including an interactive Kodak Photo-CD Portfolio technique with conventional information regarding heart failure patients' knowledge. METHODS: One hundred and thirty heart failure patients discharged from hospital were randomised to receive either conventional information or additional structured education with a follow-up of 6 months. Difference in knowledge was tested by questionnaire after 6 months. RESULTS: At the end of the study there was a significant difference in the intervention group (n = 50) compared to the control group (n = 58) regarding knowledge as tested by a questionnaire. Of maximal 28 points the intervention group attained 17.2 points (mean) and the control group 14.3 points (mean), 95% confidence interval for difference 1.0-4.7 points (P = 0.0051). CONCLUSIONS: Two to 3 hours of systematic education improved heart failure patients' knowledge on essential issues. High age does not preclude the introduction of a new technique for patient education.

Health care costs of heart failure: results from a randomised study of patient education.

BACKGROUND: Heart failure is a serious syndrome with a bad prognosis. Hospitalisation is common and readmittance rate is high; factors which influence the cost of care and treatment. Only scarce data on detailed patient materials regarding health care costs are known. AIMS: To describe in detail the health care costs for heart failure patients. METHODS: Costs for patients (n=108) who completed a randomised education trial were studied for 6 months after hospital discharge. Costs for hospital stay, out-patient visits, diagnostic tests and procedures, laboratory analyses and drug treatment were calculated. Official unit prices list used to reimburse providers of cross-boundary health services and prices for drugs in the Swedish Drug Compendium were employed. RESULTS: The total cost for a heart failure patient was approximately 20000 SEK (2564 US$, 7.80 SEK=1 US$) for 6 months. There was a 27-fold variation between patients. There was no relation between age or sex and cost. In decreasing order cost for hospitalisation was followed by costs for out-patient visits, diagnostic tests and procedures, laboratory analyses and drugs. CONCLUSION: Hospitalisation was the largest part of the total cost and there was a large inter-individual variation. Efforts to reduce the economic burden should be focused on hospitalisation. Due to skewed distribution, individual data must be considered in the analysis of the efforts.

Non-compliance and knowledge of prescribed medication in elderly patients with heart failure.

AIMS: To determine the extent of non-compliance to prescribed medication in elderly patients with heart failure and to determine to what extent patients recall information given regarding their medication. METHODS AND RESULTS: Non-compliance and knowledge of prescribed medication was studied in 22 elderly heart failure patients [mean age 79 +/- 6 (range 70-97); 14 (64%) male], using in-depth interviews performed 30 days after having been prescribed medication. All patients received standardised verbal and written information regarding their medication. Only 12 (55%) patients could correctly name what medication had been prescribed, 11 (50%) were unable to state the prescribed doses and 14 (64%) could not account for when the medication was to be taken, i.e. at what time of day and when in relation to meals the medication was to be taken. In the overall assessment six (27%) patients were found non-compliant and 16 (73%) patients were considered as possibly being compliant with their prescribed medication. CONCLUSIONS: Non-compliance was common in elderly heart failure patients, as were shortcomings in patients knowledge regarding prescribed medication, despite efforts to give adequate information. There exists a need for alternative strategies to improve compliance in these patients.

Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine beta-synthase deficiency.

Homocysteine is an amino acid considered to cause vascular injury, arteriosclerosis, and thromboembolism. Total plasma homocysteine (free and protein-bound) was found to be twice as high in asymptomatic vitamin B12-deficient subjects (23.8 +/- 3.8 mumol/L, means +/- SEM, n = 20) as in controls (11.5 +/- 0.9 mumol/L, P less than .0001, n = 21), and higher than in heterozygotes for homocystinuria due to cystathionine beta-synthase deficiency (13.8 +/- 1.6 mumol/L, P less than .01, n = 14), who were recently shown to be much more common among patients with premature vascular disease than expected. Eight (40%) vitamin B12-deficient and two (14%) heterozygote subjects had significant homocysteinemia (greater than mean +2 SD for controls). After administration of hydroxycobalamin to vitamin B12-deficient subjects, homocysteine levels decreased to normal (-49%, 12.2 +/- 1.5 mumol/L, P less than .0001, n = 20). Thus, if homocysteine does cause vascular injury, theoretically vitamin B12-deficiency might be associated with an increased frequency of vascular disease.

Left ventricular atrioventricular plane displacement: an echocardiographic technique for rapid assessment of prognosis in heart failure.

OBJECTIVE: To assess the prognostic value of atrioventricular plane displacement in heart failure patients. DESIGN: Patients were followed prospectively for one year after atrioventricular plane displacement determination. SETTING: Malmö University Hospital, with a primary catchment area of 250,000 inhabitants. PATIENTS: 181 patients with a clinical diagnosis of heart failure; age 75.7 (SD 5.2) years, duration of heart failure 2.7 (5.7) years; 100 men, 81 women. MAIN OUTCOME MEASURES: Mortality in relation to atrioventricular plane displacement. RESULTS: Total mortality was 22.7% (41/181), and was highly significantly (P = 0.001) related to atrioventricular plane displacement. Mortality within prospectively defined categories of displacement was: > or = 10.0 mm, 0% (0/19); 8.2 to 9.9 mm, 10.3% (3/29); 6.4 to 8.1 mm, 19.4% (12/62); and < 6.4 mm, 36.6% (26/71). The groups were similar in age, sex, angiotensin converting enzyme inhibitor and beta blocker treatment, and cause and duration of heart failure. CONCLUSIONS: Mortality in heart failure is strongly related to atrioventricular plane displacement.

Influence of coronary nursing management follow up on lifestyle after acute myocardial infarction.

OBJECTIVE: To examine the ability of a secondary prevention programme to improve the lifestyle in myocardial infarction patients aged 50-70 years. DESIGN: Habitual physical activity, food habits, and smoking habits were assessed from questionnaires at admission to hospital and at the one year follow up. Initially, all patients were invited to join an exercise programme and were informed about cardiovascular risk factors. Four weeks after discharge from the hospital, 87 patients were randomised to follow up at the coronary prevention unit by a special trained nurse (the intervention group), and 81 to follow up by their general practitioners (the usual care group). After randomisation, the intervention group was educated about the effects of smoking cessation, dietary management, and regular physical activity. The intervention group also participated in a physical training programme two to three times weekly for 10-12 weeks. MAIN RESULTS: 89% of the patients referred to the intervention group improved their food habits compared with 62% of the patients referred to the usual care group (P = 0.008). Furthermore, 50% of the smokers referred to the intervention group stopped smoking compared to 29% in the usual care group (P = 0.09). Changes in physical activity did not differ between the groups. CONCLUSIONS: This secondary prevention programme based on a nurse rehabilitator was successful in improving food habits in patients with acute myocardial infarction. Initiating the smoking cessation programme during the hospital stay followed by repeated counselling during follow up might have improved the results. The exercise programme had no advantage in supporting physical activity compared to usual care.

Cost effective management programme for heart failure reduces hospitalisation.

OBJECTIVE: To study the effects of a management programme on hospitalisation and health care costs one year after admission for heart failure. DESIGN: Prospective, randomised trial. SETTING: University hospital with a primary catchment area of 250,000 inhabitants. PATIENTS: 190 patients (aged 65-84 years, 52.3% men) hospitalised because of heart failure. INTERVENTION: Two types of patient management were compared. The intervention group received education on heart failure and self management, with follow up at an easy access, nurse directed outpatient clinic for one year after discharge. The control group was managed according to routine clinical practice. MAIN OUTCOME MEASURES: Time to readmission, days in hospital, and health care costs during one year. RESULTS: The one year survival rate was 71.8% (n = 79) in the control group and 70.0% (n = 56) in the intervention group (NS). The mean time to readmission was longer in the intervention group than in the control group (141 (87) v 106 (101); p < 0.05) and number of days in hospital tended to be fewer (4.2 (7.8) v 8.2 (14.3); p = 0.07). There was a trend towards a mean annual reduction in health care costs per patient of US$1300 (US $1 = SEK 7.76) in the intervention group compared with costs in the controls (US$3594 v 2294; p = 0.07). CONCLUSIONS: A management programme for patients with heart failure discharged after hospitalisation reduces health care costs and the need for readmission.

Effects of thrombin, acetyl salicylic acid and prostaglandins on spontaneous efflux of norepinephrine and beta-thromboglobulin from platelets in calcium/magnesium deficient environment.

The effect of different substances on the spontaneous efflux of 14C-norepinephrine (14C-NE) and beta-thromboglobulin (beta TG) from platelets in Ca2+ - and Mg2+ - free buffer was tested. Addition of increasing concentrations of thrombin (0.015-0.625 U/ml) resulted in an immediate increase of 14C-NE detectable in the supernatants, but the slopes of the efflux curves from 10 min after thrombin addition were almost identical and parallel with the slope before thrombin addition. Also beta-thromboglobulin was steadily released after thrombin addition. Prostaglandin E1 and prostacyclin in concentrations that gave a 30-fold increase in cAMP accumulation resulted in a moderate decrease in efflux of 14C-NE from 10 to 30 min but did not influence the efflux thereafter up to 80 min. Acetyl salicylic acid in vivo and in vitro (200-500 mumol/l) did not influence the efflux of 14C-NE or beta TG. The conclusions are that factors known to exert considerable effects on aggregation, desaggregation and acute release produce only transitory effects in a Ca2+ - and Mg2+ - free environment and that the basal efflux of alpha-granule components seems to be a stable process.

The effect of excess daily methionine intake on plasma homocysteine after a methionine loading test in humans.

Impaired homocysteine metabolism might be a risk factor for vascular disease. Peroral methionine loading and post-load determination of methionine and homocysteine in plasma has frequently been used for identifying subjects with genetically impaired homocysteine metabolism. However, a methionine-rich diet induces a more efficient homocysteine catabolism in the rat, which suggests that humans on diets with differing methionine content might respond differently to the methionine loading test. To study this we performed methionine loading in six healthy subjects before and after 2 wk of excessive daily methionine intake (300% of normal). On each occasion plasma homocysteine and methionine were measured at several intervals post-load. However, neither the methionine clearance nor the post-load homocysteine concentrations were affected by excess methionine. We conclude that variations in the daily methionine intake will not influence the methionine loading test.

Plasma beta-hexosaminidase isoenzymes A and B in patients with cerebral infarction.

We determined plasma activity of the isoenzymes of beta-hexosaminidase (Hex) in 151 patients with cerebral infarction, since earlier findings have shown a relation between Hex isoenzymes and risk factors for vascular disease in normal subjects. Compared with 206 control subjects, an elevated level of plasma Hex isoenzymes was found in patients with cerebral infarction, particularly females. However, there was no relation to the clinical subtypes of diagnosis or to the presence of any risk factors for vascular disease, such as carotid artery stenosis, major potential cardio-embolic risk factors on echocardiography, hypertension, heart disease, diabetes mellitus or tobacco smoking. Instead, our findings indicate that Hex isoenzymes in patients with cerebral infarction are more influenced by the level of serum aspartate aminotransferase and blood glucose. The main conclusion is that the liver function as reflected by the level of liver enzymes and glucose metabolism are the major determinants of Hex isoenzymes in plasma.

Prognostic significance of changes in left ventricular systolic function in elderly patients with congestive heart failure.

BACKGROUND AND DESIGN: The prognostic significance of changes in left ventricular systolic function over time is unknown in elderly patients with heart failure. We prospectively examined the relation between 1-year changes in left ventricular systolic function by echocardiographic determination of atrioventricular plane displacement (AVPD), and subsequent 2-year mortality and morbidity in elderly patients with heart failure. AVPD determination allows for left ventricular function to be adequately assessed even when image quality is poor, as is common in the elderly. METHODS: AVPD was measured at baseline and 1 year in 123 patients with heart failure (age 76.0 +/- 5.4 years). An AVPD change of 1 mm or more (corresponding to an ejection fraction change of 0.05) was considered significant. RESULTS: AVPD decreased in 26 patients (21%), increased in 46 (37%), and was unchanged in 51 (42%). During a 2-year follow-up (from the 1-year examination) mortality, total hospitalizations, and hospitalizations for heart failure (35% of all hospitalizations) did not differ significantly between the three groups. Patients (n = 80) with AVPD of 8.2 mm or less (corresponding to left ventricular ejection fraction of 0.40 or less) at the 1-year examination demonstrated a higher mortality than patients with AVPD greater than 8.2 mm (43.8 versus 23.3%; P = 0.031), and also had more hospitalizations and days in hospital due to heart failure (1.0 +/- 1.5 versus 0.4 +/- 0.8, P = 0.020 and 10.4 +/- 15.6 versus 4.6 +/- 10.6, P = 0.033, respectively). CONCLUSIONS: Left ventricular function was readily assessed in all patients by determination of AVPD. Our results indicate that single but not serial assessment of left ventricular systolic function by determination of AVPD is of value in assessing the prognosis in elderly patients with heart failure.

beta-Hexosaminidase isoenzymes A and B in middle-aged and elderly subjects: determinants of plasma levels and relation to vascular disease.

Plasma/serum beta-hexosaminidase (Hex) activity is known to be increased in chronic alcoholism, liver disorders, pregnancy and diabetes mellitus. Hex activity also shows an association with risk factors for vascular disease and heredity for arteriosclerosis. There are several isoenzymes of Hex. Using an enzyme immunoassay for Hex isoenzymes (Hex A and Hex B) we studied possible determinants of Hex isoenzymes and their relation to vascular disease in randomly invited (n = 244) 35-95-year-old men and women. In both sexes there were significant age-related increases in Hex activities and men exhibited higher activity of both isoenzymes. Both Hex isoenzymes correlated with age, systolic blood pressure, serum triglycerides and liver enzymes, whereas Hex A was distinguished from Hex B by its stronger correlation with blood glucose. In multiple linear regression analysis Hex A was explained to 20.7% by blood glucose, age, serum aspartate aminotransferase and glutamyl transpeptidase. Hex B was explained to 14% by age, serum glutamyl transpeptidase and serum triglycerides. There was no significant increase in Hex isoenzymes in subjects with hypertension, diabetes mellitus or myocardial disease, nor did current smokers exhibit any increase of these enzymes compared to non-smokers. The main conclusion in that liver function, as reflected by the level of liver enzymes and glucose metabolism, is the major determinant for Hex isoenzymes in plasma.